Levomilnacipran, Vilazodone, and Vortioxetine Provide Similar Benefits, Adverse Effects as Standard Antidepressants

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Safety and efficacy of levomilnacipran, vilazodone, and vortioxetine are compared with second-generation antipsychotics for major depressive disorder.

Among patients treated for major depressive disorder (MDD), levomilnacipran, vilazodone, and vortioxetine are not associated with significantly greater benefits or harms compared with standard second-generation antidepressant medications, according to findings from a retrospective review published in the Journal of Affective Disorders.

In this study, investigators reviewed 24 randomized controlled trials and controlled observational studies that assessed patient response to vilazodone vs citalopram and vortioxetine vs duloxetine, paroxetine, or venlafaxine XR (extended release). Using these data, the investigators performed network meta-analyses on placebo- and active-controlled randomized controlled trials included in a connected network that featured homogeneous study populations.

Overall, findings from the head-to-head trials as well as network meta-analyses revealed similar efficacy rates with levomilnacipran, vilazodone, and vortioxetine when compared with other second-generation antidepressants, including citalopram, duloxetine, paroxetine, bupropion, and fluoxetine.

No significant differences between patients treated with either therapy were found in terms of treatment response. In one study, a higher proportion of patients with MDD managed with vilazodone experienced vomiting (6.6% vs 1.8%; relative risk [RR] 3.73; 95% CI, 1.41-9.86 [self-calculated]) and diarrhea (26.5% vs 10.6%; RR 2.49; 95% CI, 1.69-3.67 [self-calculated]) vs patients managed with citalopram.

Adverse event rates were similar overall; however, some studies did reveal statistically significant and numeric differences. Additionally, another study found vortioxetine to be associated with higher rates of vomiting (9.0% vs 3.5%; RR 2.54; 95% CI, 0.81-8.00 [self-calculated]) and nausea (38.0% vs 33.6%; RR 1.13; 95% CI 0.79-1.62 [self-calculated]) compared with venlafaxine XR-treated patients, but these rates did not reach statistical significance.

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Considering that this review and meta-analysis was restricted to only adult patients with MDD, these findings may not be generalizable to other patient populations. In addition, investigators assessed only studies published in English, further limiting the findings.

Because no overall differences were found between the studied medications and other second-generation antidepressants, the investigators suggest that physicians treating those with MDD should “consider patient preferences following a discussion of the advantages and disadvantages and the feasibility (eg, costs, likely adherence) of different antidepressants.”


Wagner G, Schultes MT, Titscher V, Teufer B, Klerings I, Gartlehner G. Efficacy and safety of levomilnacipran, vilazodone and vortioxetine compared with other second-generation antidepressants for major depressive disorder in adults: a systematic review and network meta-analysis. J Affect Disord. 2017;228:1-12.